**3. Treatment of COVID-19**

To date, no pharmacological intervention has been shown to be effective and safe to ensure its use in the routine treatment of patients with COVID-19; therefore, ideally, these patients have been treated in the context of clinical trials and guidelines for good clinical practice. In newly emerging diseases, such as COVID-19, especially in a pandemic situation, interventions are mainly performed *based on in vitro experiments, personal experiments,* and small limited observational studies. The management of the disease depends largely on symptomatic and supportive treatments [14].

Worldwide, several pharmacological interventions have been proposed for COVID-19, such as anticoagulants, antimicrobials, chloroquine, hydroxychloroquine, convalescent plasma, remdesivir, and tocilizumab [14]. For severely or critically ill patients with acute respiratory distress syndrome (ARDS) and sepsis, in addition to supplemental oxygen, mechanical ventilation and specific therapies for ARDS, antiviral and antibiotic treatments should also be considered [15, 16].

## **3.1 Steroids**

The use of systemic corticosteroid therapy in the treatment of infectious diseases is controversial, however, widely used. Corticosteroids have received worldwide attention as a potentially effective treatment for COVID-19 infection [15]. In the COVID-19 Randomized Trial of Therapy (RECOVERY), the use of dexamethasone resulted in lower mortality rates in individuals with COVID-19 who received mechanical ventilation or supplemental oxygen [17]. In the CoDEX study in patients with COVID-19 and moderate or severe ARDS, the use of dexamethasone resulted in a statistically significant increase in the number of days without mechanical ventilation, but without impact on mortality [18].

Pathologies that present an increase in endogenous levels of glucocorticoids (CG) are sepsis, cachexia, metabolic acidosis, and severe insulinopenia. GC-induced muscle atrophy is characterized by rapidly contracting glycolytic muscle atrophy, decreased fiber cross-sectional area, and reduced myofibrillar protein content [19, 20]. Glucocorticoids lead to an imbalance between the rate of synthesis and degradation of proteins. Dexamethasone, a synthetic glucocorticoid, stimulates skeletal muscle atrophy by promoting protein degradation [19] through the ubiquitin-proteasome pathways and by inhibiting protein synthesis via Akt/(mTOR) [21].

According to Shang et al. [22], patients with COVID-19 release elevated cytokine levels, showing that alveolar damage is steroid-responsive. The RECOVERY study established that dexamethasone can significantly decrease mortality in severe cases of COVID-19, especially in critical conditions when ventilatory support is necessary, presumably because the severity of lung injury reflects worsening of the hyperinflammation. The reason for dexamethasone to be chosen included its antiinflammatory potency, lack of mineralocorticoid effect, and longer action profile [23]. Pharmacological responses require exposure to high doses of corticosteroids, *and in vitro studies have shown* a higher response with methylprednisolone than with dexamethasone [24], and this preference is sustained when the inflammatory pathway and characteristics of the different corticosteroids are considered. In addition, treatment with methylprednisolone for a shorter period may also minimize systemic side effects [25]. The trial of Ko et al. [26], provided evidence that the mortality benefit of dexamethasone in severe COVID-19 is not drug-specific but

rather the general anti-inflammatory effect of corticosteroids. In this study, the higher anti-inflammatory potency of methylprednisolone showed additional mortality benefits, especially in patients who required mechanical ventilation.

The Brazilian guideline for the pharmacological treatment of hospitalized patients reviewed several studies worldwide, bringing a strong recommendation for the use of dexamethasone (6 mg/day for 10 days) only in individuals who are under the use of supplemental oxygen therapy since at the Brazilian level, this drug has good tolerance on the part of the patient and low cost for health institutions. There is no evidence for the use of routine corticosteroids in patients with COVID-19, especially, this should still be avoided within the first 7 to 10 days of the onset of the symptoms, when the host response is fighting the viral infection. Some evidence suggests retardation in viral clearance when corticosteroids are used early. The potential benefit of its use would be in patients with moderate to severe ARDS, in selected cases and without suspicion of uncontrolled bacterial infection, 10–14 days after the onset of COVID-19 symptoms. The doses used in the studies ranged from 10 mg to 20 mg of dexamethasone and 40 mg to 120 mg of methylprednisolone per day for 5–10 days [14].

The Brazilian recommendation is in accordance with the WHO guideline Corticosteroids for COVID-19 launched in September 2020, which reviewed metaanalyses and randomized trials with data from more than 7,000 patients. The WHO panel recommends the use of oral or intravenous glucocorticoids for 7 to 10 days in patients with severe and critical COVID-19, defined by the presence of signs of respiratory distress, increase in respiratory rate, hypoxemia, necessity of vasopressor therapy, and/or mechanical ventilation, regardless of their hospitalization status. The recommendation is supported by evidence of 6.7 to 8.7% reduction in 28-day mortality and reduction in the need for invasive mechanical ventilation. Different GC can be selected, according to availability and observing equivalent doses. The daily dose of 6 mg of dexamethasone is equivalent to 40 mg of prednisone, 160 mg of hydrocortisone (e.g., 50 mg every 8 hours or 100 mg every 12 hours), or 32 mg of methylprednisolone (e.g., 8 mg every 6 hours or 16 mg every 12 hours). The panel also recommends to monitor glucose levels and other potential GC adverse effects, and not to use GC in non-severe COVID-19, due to a potential risk of increasing death in this setting. One should also adjudicate the risk of secondary and endemic infections and act to minimize their risk.

An important aspect to consider is that the increase in cortisol and bed rest act synergistically on the decrease in muscle mass. It has been demonstrated that after 28 days, healthy young individuals lost more muscles when confined to bed and received hydrocortisone than only at rest [27]. The restriction of movements during hospitalization of COVID-19 in the ICU is different from other clinical conditions, because the patient with COVID-19 may present deep weakness, spend hours on high-flow oxygen therapy or in ventral decubitus. A median reduction of 18.5% of the rectus femoris muscle between the first and seventh day of ICU stay may occur [28]. In addition, the study by Kirwan et al. [29] demonstrated an unadjusted risk of sarcopenia of 38.4% associated with an average time of 11 days in hospital stay by COVID-19.

One of the main side effects of GC use is hyperglycemia, and this condition is also induced by the course of critical disease [30]. The diabetogenic effect of steroids in susceptible patients can aggravate the problem of anabolic resistance. The hyperglycemia of the critically ill patient is related to insulin resistance, that is, the impossibility of insulin to stimulate glucose uptake in skeletal muscle or to inhibit gluconeogenesis in the liver. During critical disease, the abrupt development of hyperglycemia involves complex interactions between some counterregulatory hormones (glucagon, catecholamines, growth hormone, and cortisol), adipokines, and inflammatory cytokines that cause increased glucose production by the liver and insulin resistance in tissues. This hyperglycemia can affect the functions of respiratory muscles, leading to respiratory muscle weakness acquired in the ICU, as well as increase mortality in these patients [5]. Insulin resistance ultimately promotes a catabolic state that implies lipolysis and loss of muscle mass [31].

#### **3.2 IL-6 antagonists**

Tocilizumab is an interleukin 6 inhibitor approved for the treatment of rheumatoid arthritis, giant cell arteritis, and cytokine release syndrome during chimeric antigen receptor (CAR-T) T-cell therapy. Interleukin 6 is an inflammatory cytokine that exerts its effects on the liver and lymphocytes, inducing acute phase reagents such as C-reactive protein, fibrinogen, and hepatocytes hepcidin, and promotes the differentiation of cytotoxic T cells CD4 (T helper 17) and CD8 and antibody production. Interleukin 6 plays an important role in controlling viral infections such as influenza A, acute severe respiratory syndrome coronavirus 1, and herpes virus. In COVID-19, an increased level of interleukin 6 and C-reactive protein correlates with the severity and mortality of the disease. Thus, blocking the activity of interleukin 6 may play a role in mitigating the inflammatory response and improving clinical outcomes in patients with COVID-19 [32].

The World Health Organization's (WHO) Rapid Evidence Assessment Working Group (REACT) developed a protocol to perform a prospective meta-analysis of IL-6 antagonists in patients hospitalized by COVID-19. The IL-6 antagonists investigated were monoclonal antibodies that bind to soluble, membrane-bound IL-6 receptors (e.g., tocilizumab and sarilumab) or directly to IL-6 (e.g., siltuximab). Administration of IL-6 antagonists, compared to usual treatment or placebo, was associated with lower all-cause mortality in 28 days [33]. Tocilizumab is a humanized antibody against IL-6 and has been used in patients with pronounced cytokine storm. Patients with rheumatoid arthritis who regularly use this medication have demonstrated that long-term treatment with tocilizumab leads to increased muscle mass, as assessed with *dual X-ray absorptiometry* (DEXA) [34]. Tocilizumab reduces the risk of mechanical ventilation in hospitalized patients [35] and also reduces all-cause mortality on day 28 compared to standard treatment alone or with placebo [36] (**Figure 5**).

According to the available studies [17, 37], tocilizumab was recommended by Brazilian treatment guidelines for patients with COVID-19, who are using NIV (noninvasive mechanical ventilation) or CNAF (high flow nasal catheter) and not recommended in patients under mechanical ventilation. To date, the studies have not shown clear benefits in patients under mechanical ventilation; however, there is a tendency to prescribe it in the first 24 hours of IMV, at medical discretion. However, the authors indicate that the package leaflet of this medicine does not present this indication [28], that is, its use in MV *would be off-label,* and access to this drug may be limited by availability and also financial reasons.

The indicated dosage is 8 mg/kg, with a maximum administration of 800 mg, and a second application should only be performed after careful medical reassessment. Evidence also suggests that the benefits of tocilizumab are associated with corticosteroid co-administration [17] and may preferably be used in patients with increased inflammatory markers (C-reactive protein test, ferritin, and lactic dehydrogenase).

#### **Figure 5.**

*Tocilizumab mechanism of action. Tocilizumab is a recombinant humanized monoclonal antibody, which acts as an interleukin 6 receptor antagonist (IL-6), blocking the transduction of the signal of this proinflammatory cytokine, preventing the dimerization of GP130 in the cell membrane and, consequently, blocks the proinflammatory effects of IL-6. In addition, it has the ability to dissociate IL-6/IL-6R complexes that have already formed. The IL-6 receptor has two presentations: membrane-bound IL-6 receptor and soluble IL-6 receptor. IL-6 is binding with IL-6R for the formation of a complex, which is coupled to the transmembrane protein gp130 so that signal transduction occurs and pro-inflammatory function is performed. Source: Figure of the authors.*

For patients with signs of bacterial infection, with latent infections such as tuberculosis or parasitic, care should be given to the possibility of reactivation of these with the administration of tocilizumab. In immunosuppressed patients, its use should be with caution, and in neutropenic individuals (<500 cells/mm3 ), thrombocytopenic (< 50,000 platelets/mm3 ) or with transaminases at levels five times greater than physiological value, tocilizumab should not be used at all [14].

In addition to tocilizumab, other trials that use Casirivimab and Imdevimab are presenting significantly promising results, however, only in patients in the early stages of the disease [38, 39] and not in hospitalized patients. Recommendations of the treatment panel for COVID-19 for the treatment of outpatients, by order of preference, are nirmatrelvir enhanced with ritonavir (Paxlovid) (AIIa) and remdesivir (BIIa). Other alternative medicines, such as Bebtelovimab (CIII) and Molnupiravir (IIC), should be used only when none of the first-rate medicines are available.

It is also worth noting that the treatments with antiviral drugs that the WHO panel against indicates are interferons for outpatients (AIIa), interferon alpha or lambda for hospitalized patients (AIIa), Ivermectin (AIIa), Nitazoxanide (BIIa), Chloroquine or hydroxychloroquine and/or azithromycin for hospitalization (AI) and not hospitalization situation (AIIa), Lopinavir/ritonavir and other HIV protease inhibitors for hospitalized patients (AI) and outpatients (AIII) and systemic interferon beta for hospitalized patients (AI). Due to these concerns and data gaps, Molnupiravir should be provided only to non-severe patients with COVID-19 at higher risk of hospitalization. Typically, they are people who have not received COVID-19 vaccination, elderly people with immunodeficiencies or people living with chronic diseases.

Treatment with anti-SARS-CoV-2 mAbs should be considered for patients with mild-to-moderate COVID-19 who are hospitalized, considering that the risk of

*COVID-19: From Pathophysiology to Treatment DOI: http://dx.doi.org/10.5772/intechopen.107146*

progression to severe COVID-19 in high-risk patients is substantially higher for those who are not vaccinated. It is also interesting to note that severely immunocompromised patients may have prolonged replication of SARS-CoV-2, leading to faster viral evolution, with consequent worse clinical outcomes. Anti-SARS-CoV-2 monoclonal antibodies (mAbs) have their results variable, depending on the circulating strain. As a suggestion, the use of anti-SARS-CoV-2 mAbs is based on current knowledge of SARS-CoV-2 in vitro activities. At the moment, the recommendations of the panel's anti-SARS-CoV-2 mAb are for the treatment of patients with mild-to-moderate COVID-19 who are at high risk of progressing to severe disease.

Intravenous Bebtelovimab has its use only for patients aged ≥12 years as an alternative therapy when nirmatrelvir (Paxlovid) and remdesivir potentiated with ritonavir are not available, viable to use, or clinically appropriate (CIII). Treatment should be started as soon as possible and within 7 days after the onset of symptoms. Anti-SARS-CoV-2 mAbs should be administered in an environment where severe hypersensitivity reactions such as anaphylaxis can be controlled. Patients should be monitored during the infusion and observed for at least 1 hour after infusion.

#### **3.3 Anticoagulants**

The care team should pay attention to the development of signs and symptoms of thromboembolic events. Due to this risk, patients hospitalized due to COVID-19 should receive prophylaxis of thromboembolism according to their risk stratification, according to current hospital protocols, for presenting in a high state of hypercoagulability, with a high rate of thromboembolic events being observed in observational and postmortem clinical studies. The dose to be used may vary according to the chosen class, for example, enoxaparin 40 to 60 mg SC once a day or the unfractionated heparin 5,000IU SC two to three times a day. Although evidence for pharmacological prophylaxis in the context of COVID-19 is limited, the intervention is low cost and well-tolerated, with the potential to avoid events of high clinical importance. Heparin should not be used in the case of contraindications of high risk of bleeding, active bleeding, and severe thrombocytopenia [40].

Critically ill patients have a strong recommendation for prophylactic doses for venous thromboembolism with anticoagulant (mainly with the use of vasoactive drugs, on hemodialysis or using CNAF, NIV, or MV), according to the Brazilian guidelines for pharmacological treatment for COVID-19. But there is no recommendation for the use of intermediate doses in patients without signs of thromboembolism. Anticoagulants should be used, following a careful assessment of bleeding risk and presence of thrombocytopenias [14].

In a study evaluating 42 patients, all using immunosuppressant or glucocorticosteroids, with severe to moderate COVID-19, with 21 patients receiving low-molecular weight heparin and 21 controls, there was a significant reduction. In IL-6 dosage and increased lymphocytes. The results of this study contribute to the use of low-molecular weight heparin as a potential therapeutic drug for the treatment of COVID-19. Changes in D-dimer levels and fibrinogen degradation products in the group that received heparin before and after treatment were significantly different from those in the control group (P = 0.035). Together, IL-6 levels have also been reduced after heparin treatment (P = 0.006), indicating that, in addition to other beneficial properties, it can exert an anti-inflammatory effect and partly attenuate the virus-induced "cytokine storm" [41].

There is no indication of routine use of anticoagulants in post-discharge due to COVID-19. The indication of the use of anticoagulants in a post-discharge setting

should follow the same criteria as for patients without COVID-19, according to institutional protocols.

#### **3.4 Antimicrobials (antibiotics)**

Patients with COVID-19 without signs of sepsis or infection are not recommended for antibiotic therapy. However, individuals who present potential infectious foci on admission, with suspected sepsis, presenting or not being diagnosed for COVID-19, are indicated for the use of antibiotics (empirically). Also, patients with worsening due to COVID-19, who require care in intensive care units, are exposed to processes that potentiate the risk of infection, such as mechanical ventilation, bladder catheter, and arterial and venous accesses, which can lead to the need for the use of antibiotic therapy to this population [14].

To date, there is no randomized clinical trial evaluating the effectiveness of empirical antibacterials in patients with COVID-19 without evidence of bacterial infection, that is, clinical data are insufficient to demonstrate benefits or risks in the use of antibacterials in patients with COVID-19 without evidence of bacterial infection, so in the absence of evidence, there is no basis to indicate prophylactic antibacterials in patients with COVID-19. In addition to the absence of evidence of benefit, this practice may result in adverse events, increased antimicrobial resistance, and costs. There are no adequate data on bacterial co-infection in patients with COVID-19; however, it should be noted that the overlap of infections is possible to occur, mainly due to immunosuppression and exposure to the hospital environment, often colonized by multidrug-resistant germs. It is understood that these patients should receive antibacterials in a similar way to patients without COVID-19, following local protocols.

In the meta-analysis of Lanford [42] with 3,338 eligible patients, bacterial coinfection (estimated at presentation) was identified in 3.5% of patients (95% CI 0.4–6.7%) and secondary bacterial infection in 14.3% of patients (95% CI 9.6–18.9%). The overall proportion of patients with COVID-19 with bacterial infection was 6.9% (95% CI 4.3–9.5%). Bacterial infection was more common in critically ill patients (8.1%, 95% CI 2.3–13.8%). Since bacterial co-infection is relatively infrequent in patients hospitalized with COVID-19, therefore, most of these patients may not require empirical antibacterial treatment, reinforcing the guidelines of following institutional protocols for sepsis.

#### **3.5 Oxygen therapy**

Lung injury due to the new coronavirus resembles other causes of ARDS, but initial clinical features include more evident hypoxemia and loss of dyspnea perception. Due to the various forms of presentation of COVID-19, oxygen supplementation levels may vary according to clinical and laboratory signs. According to Guan [9], almost half (42%) of patients admitted to the hospital environment will require supplemental oxygen therapy. Nationwide, in the first five months of the pandemic, 49% of those infected required noninvasive respiratory support [43].

Oxygen therapy is defined as oxygen therapy, the administration of oxygen above the ambient air concentration (~21%), aiming to maintain adequate oxygenation of tissues. Its use has the potential to correct hypoxemia by reducing cardiorespiratory work overload [18]. Therefore, oxygen therapy is one of the treatments for the clinical condition in more severe cases of SARS-CoV-2 infection, since patients presenting hypoxemia or signs of respiratory effort may benefit from its use, either via the ocular

#### *COVID-19: From Pathophysiology to Treatment DOI: http://dx.doi.org/10.5772/intechopen.107146*

nasal catheter, mask with a non-rebreathing oxygen mask, noninvasive ventilation (NIV), or high-flow nasal catheter (HFNC) [44]. If there is a need for oxygen therapy, it is recommended to be given its administration according to peripheral oxygen saturation (SpO2), with a strong recommendation of its onset when SpO2 <90%, in order to keep it between 92% and 96% in previously healthy patients and between 88% and 92% for patients with chronic lung disease [45].

### *3.5.1 High flow nasal cannula – HFNC*

Prior to the COVID-19 pandemic, HFNC was already recommended in patients with moderate respiratory failure [46] and demonstrated efficacy in the treatment of acute hypercapnic respiratory failure [47, 48]. In CNAF, the supplementary supply of oxygen allows the administration of high flows (up to 60 liters per minute) and precise oxygen concentrations (21% to 100%) [49]. Even if there is no routine recommendation, when HFNC is indicated, it can be used in selected patients with hypoxemic respiratory failure associated with COVID-19, who have clinical signs and symptoms such as SpO2 < 93%, PaO2/FiO2 <300 mmHg, and respiratory rate > 25 incursions per minute [50].

#### *3.5.2 Noninvasive mechanical ventilation – NIV*

NIV contributes to the improvement of oxygenation and reduction of respiratory work and may prevent orotracheal intubation [51]. In viral pandemic disease, NIV has no recommendations for the treatment of hypoxemic respiratory failure [52], and depending on the interface used, large aerosol dispersion (COVID-19 dissemination medium) [53] can occur, so its indication should be judicious, and its application should be closely monitored.

The success of NIV to avoid intubation seems to be associated with patients with PaO2/FiO2 ratio > 100 mmHg and without multiple organ failure (APACHE < 20 score). During the first 30 minutes, ventilometry monitoring is very important, because a minute volume > 10l/min, current volume > 9 ml/kg predicted, respiratory rate > 25 irpm, requiring final expiratory positive pressure > 10 cmH20 with FiO2 > 50%, indicate its failure [50, 54].

### *3.5.3 Invasive mechanical ventilation – IMV*

Among individuals infected with SARS-CoV-2, approximately 80% of the cases are asymptomatic, 15% present a more severe form (requiring supplemental oxygen), and 5% evolve to the most critical form, requiring advanced life support [41, 44]. This can occur mainly in patients with chronic heart or lung diseases, diabetes, obesity (BMI > 40), and in the elderly [51]. A recent study with biopsy of the diaphragm muscle showed the expression of ECA 2 and viral infiltration SARS-CoV-2 in the diaphragm of a subset of patients and histological evidence for the development of fibrosis [41].

The findings in the severe form of COVID-19 meet the diagnostic criteria for ARDS [55], and when hypoxemia worsens, hypercapnia, acidemia, respiratory fatigue, hemodynamic instability, or even mental status alterations, intubation should be strongly considered [50, 56], consequently requiring invasive mechanical ventilation (IMV). For those who need IMV, the objectives of this therapy are based on: maintenance of gas exchange (by correction of hypoxemia and respiratory acidosis

associated with hypercapnia), reduction of respiratory work (with reversal or prevention of fatigue of respiratory muscles), and application of other specific and necessary treatment routes [57].

The long-term prognosis of patients who survive intensive care is affected by physical disabilities, cognitive impairments, and mental disorders that may occur after discharge from the ICU [58]. In relation to muscle mass loss, it may occur more frequently in older adults and patients with comorbidities who are more likely to have pre-existing catabolism. In addition, these groups of patients may be prone to develop more intense catabolic responses due to COVID-19 and prolonged ICU stay [59].

In addition to the systemic inflammatory process with cytokine release that contributes to the evolution of ARDS in critically ill patients with COVID-19, these patients also have an increased risk for weakness and sarcopenia due to the same inflammatory mechanism of loss of muscle mass. Associated with these factors, the length of stay on mechanical ventilation is high (mean of 11.7 days). About 75%–80% of patients hospitalized with COVID-19 have extended hospital stays, with about 21 days. When admitted to the ICU, they may have multiple organ failures, including ARDS, acute kidney injury, heart injury, and liver dysfunction [60]. Evidence has shown that organic dysfunction is highly associated with muscle dysfunction [61]. Additionally, some of these patients have associated comorbidities, such as advanced age, renal dysfunction, hypertension, diabetes, and heart disease, which may contribute to the incidence of weakness and sarcopenia. Thus, critical patients with COVID-19 may face a vicious cycle, in which the severity of the disease itself, the presence of comorbidities, prolonged invasive ventilatory support, and the use of sedatives and neuromuscular blockers may contribute to the development of weakness, sarcopenia, and functional dysfunctions in the short and long term [60].

### **4. Final considerations**

Research and science are essential for the successful conduction of the COVID-19 pandemic. In this context, discovering the entry mechanism of the virus into a cell, the expected response of the host, and especially the exacerbated response in the form of the cytokine storm were fundamental for the initiation of clinical reasoning of diagnostic and therapeutic approaches. The unfavorable evolution of the clinical presentation of COVID-19 has led and still leads countless patients to need treatment in the intensive care unit (ICU), and sarcopenia and secondary infectious processes are a potential risk for the worsening of the clinical outcome [42, 62–87].

Thus, the intense scientific and technological advances in recent years of this pandemic favored the understanding and elucidation of the pathophysiology of the disease, and this knowledge is a crucial point for the use of existing drugs, such as tocilizumab, for the development of promising drugs and application of assistance protocols. The application of biomarkers, both clinical and laboratory, is differential when managing COVID-19, especially to stratify risk groups, monitor evolution, make therapeutic decisions, and in prognosis.

*COVID-19: From Pathophysiology to Treatment DOI: http://dx.doi.org/10.5772/intechopen.107146*
